A Phase 1/2 interventional study of Pazopanib and Pazopanib Hydrochloride in High Grade Sarcoma, Metastatic Leiomyosarcoma and Metastatic Malignant Peripheral Nerve Sheath Tumor, sponsored by National Cancer Institute (NCI). Terminated at 460 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2022-08-23.
Sponsored by National Cancer Institute (NCI) · Phase 1/2, Interventional, and Treatment
This phase I/II trial studies the side effects and best dose of sapanisertib and to see how well it works compared to pazopanib hydrochloride in treating patients with sarcoma that is too large to be removed (locally advanced) or has spread to other areas of the body (metastatic). Sapanisertib and pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
PRIMARY OBJECTIVES:
I. To determine the safety and maximum tolerable dose of sapanisertib (MLN0128 [TAK-228]) within this patient population. (Phase I) II. To determine the differences in progression-free survival (PFS) in patients with sarcoma who receive MLN0128 (TAK-228) as compared to pazopanib (pazopanib hydrochloride). (Phase II)
SECONDARY OBJECTIVES:
I. To evaluate adverse events. (Phase I/II) II. To evaluate overall response rate (ORR), clinical benefit rate (CBR), and duration of response (DOR). (Phase I/II) III. To evaluate time to progression (TTP) and overall survival (OS). (Phase I/II)
EXPLORATORY OBJECTIVES:
I. To evaluate PFS and secondary endpoints within patients crossing over to MLN0128 (TAK-228), upon disease progression during treatment with pazopanib. (Phase II) II. To evaluate the 4 month CBR observed within patients treated with MLN0128 (TAK-228) and grouped by histologically defined cohorts. (Phase II)
OUTLINE: This is a phase I, dose-escalation study, followed by a randomized phase II study.
PHASE I: Patients receive sapanisertib orally (PO) on days 1, 8, 15, and 22 in the absence of disease progression or unacceptable toxicity.
PHASE II: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients receive sapanisertib as in Phase I. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive pazopanib hydrochloride PO once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression may crossover to Arm I.
After completion of study treatment, patients are followed up at 4 weeks and then every 6 months for 2 years.
177 studies on the registry are indexed under Leiomyosarcoma; 35 are open to participants now.
This study's enrollment of 151 is above the median of 54 across 151 interventional studies indexed under Leiomyosarcoma.
Browse Leiomyosarcoma studies →National Cancer Institute (NCI) is the lead sponsor of 3,556 studies on the registry; 336 are open to participants now.
Of its 411 completed or terminated interventional studies of FDA-regulated products, 373 (91%) have results posted.
Counted across the registry records on this site, refreshed daily.
Inclusion Criteria:
Patients must have slides available for submission to central pathology review; this review is mandatory prior to registration to confirm eligibility and proper cohort assignment
HISTOLOGIC COHORT 3: Other (either malignant peripheral nerve sheath tumor or synovial sarcoma); during the phase II portion of the study, enrollment will be limited to maximum of 25 patients in this cohort
Patient history: patients who have any of the following are NOT eligible:
Gastrointestinal (GI):
Cardiac and vascular disorders:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Cancer that has spread from where it began to other parts of the body. “Metastatic” cancer is cancer that has spread this way.
The amount of disease can be tracked with a defined measurement, so the study can see whether it shrinks or grows. It might be a tumour measured on a scan or, in some blood cancers such as myeloma, a marker measured in blood or urine.
The criteria or the study team say which measurement counts — having no tumour visible on a scan does not by itself rule you out.
Neoadjuvant treatment is given before the main treatment (usually surgery), often to shrink a tumour. Adjuvant treatment is given after it, to lower the chance of the cancer coming back.
A line of therapy is one course of treatment, which may combine several drugs. First-line is the first course given; second-line follows when that stops working or is not tolerated.
“Two prior lines” means two courses that count separately under the study’s rules — not simply two drugs. Ask the study team if you are unsure how yours are counted.
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.
Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.
The US National Cancer Institute’s scale of how severe an adverse event is — any unwanted medical event during a study, such as a symptom, an illness or an abnormal test result, whether or not a treatment caused it. Whether it did is judged separately.
“Side effects of earlier treatment resolved to grade 1 or less” means they have settled to mild or gone.
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
A scale of how much an illness limits everyday activity. For people being assessed to join a study, scores run from 0 (fully active) to 4; lower is more active.
Studies most often ask for 0–1 or 0–2. Your doctor gives the score; the WHO scale uses the same steps. The full scale also has 5, which records death.
Cancer deposits in the brain from a cancer that started elsewhere in the body (CNS metastases include the spinal cord).
Studies differ: some leave out any brain metastases, some accept ones treated and stable for some weeks. Check what this study allows.
The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).
On an ECG, the QT interval is the time the heart’s lower chambers take to activate electrically and recover in each beat. QTc is that time adjusted for heart rate (QTcF by Fridericia’s formula, QTcB by Bazett’s). Some medicines lengthen it, and a long QTc can raise the risk of a dangerous heart rhythm.
The study may name a correction formula and a limit in milliseconds, often around 450–480.
A “mini-stroke”: temporary stroke-like symptoms caused by reduced blood flow to part of the brain, spinal cord or eye, without signs of a new stroke on a scan.
Stroke symptoms need emergency care at once, even if they go away.
The share of blood the heart’s main pumping chamber (the left ventricle) pushes out with each beat, measured by an echocardiogram (heart ultrasound) or a MUGA scan. About 50–70% is normal.
CYP3A is a group of enzymes, mainly CYP3A4, in the liver and gut that break down many medicines. Some medicines, supplements and foods (grapefruit, St John’s wort) slow them down or speed them up, which changes how much of a study drug stays in the body.
Studies list them so they can be avoided or switched; bring a list of everything you take, including supplements.
The number of neutrophils, white blood cells that help fight infection, in a given amount of blood. Too few raises the risk of infection.
It is a count, not a percentage of the white cells. Limits are written in units that mean the same: ≥ 1.5 × 10⁹/L is ≥ 1,500 per mm³ (µL). Each lab has its own reference range.
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
A yellow substance made when red blood cells are broken down, which the liver clears. A high level can mean a problem with the liver or the bile ducts.
Criteria often allow more for people with Gilbert’s syndrome, a harmless inherited condition that raises bilirubin.
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
Metastases
Cancer that has spread from where it began to other parts of the body. “Metastatic” cancer is cancer that has spread this way.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Measurable disease
The amount of disease can be tracked with a defined measurement, so the study can see whether it shrinks or grows. It might be a tumour measured on a scan or, in some blood cancers such as myeloma, a marker measured in blood or urine.
The criteria or the study team say which measurement counts — having no tumour visible on a scan does not by itself rule you out.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Adjuvant and neoadjuvant
Neoadjuvant treatment is given before the main treatment (usually surgery), often to shrink a tumour. Adjuvant treatment is given after it, to lower the chance of the cancer coming back.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Line of therapy
A line of therapy is one course of treatment, which may combine several drugs. First-line is the first course given; second-line follows when that stops working or is not tolerated.
“Two prior lines” means two courses that count separately under the study’s rules — not simply two drugs. Ask the study team if you are unsure how yours are counted.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Investigational drug or device
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Cancer (malignancy)
Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.
Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
CTCAE grade
The US National Cancer Institute’s scale of how severe an adverse event is — any unwanted medical event during a study, such as a symptom, an illness or an abnormal test result, whether or not a treatment caused it. Whether it did is judged separately.
“Side effects of earlier treatment resolved to grade 1 or less” means they have settled to mild or gone.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Childbearing potential
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ECOG performance status
A scale of how much an illness limits everyday activity. For people being assessed to join a study, scores run from 0 (fully active) to 4; lower is more active.
Studies most often ask for 0–1 or 0–2. Your doctor gives the score; the WHO scale uses the same steps. The full scale also has 5, which records death.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Brain metastases
Cancer deposits in the brain from a cancer that started elsewhere in the body (CNS metastases include the spinal cord).
Studies differ: some leave out any brain metastases, some accept ones treated and stable for some weeks. Check what this study allows.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hemoglobin (Hb)
The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
QT and QTc
On an ECG, the QT interval is the time the heart’s lower chambers take to activate electrically and recover in each beat. QTc is that time adjusted for heart rate (QTcF by Fridericia’s formula, QTcB by Bazett’s). Some medicines lengthen it, and a long QTc can raise the risk of a dangerous heart rhythm.
The study may name a correction formula and a limit in milliseconds, often around 450–480.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
TIA (transient ischaemic attack)
A “mini-stroke”: temporary stroke-like symptoms caused by reduced blood flow to part of the brain, spinal cord or eye, without signs of a new stroke on a scan.
Stroke symptoms need emergency care at once, even if they go away.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
LVEF (left ventricular ejection fraction)
The share of blood the heart’s main pumping chamber (the left ventricle) pushes out with each beat, measured by an echocardiogram (heart ultrasound) or a MUGA scan. About 50–70% is normal.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
CYP3A (CYP3A4) inhibitors and inducers
CYP3A is a group of enzymes, mainly CYP3A4, in the liver and gut that break down many medicines. Some medicines, supplements and foods (grapefruit, St John’s wort) slow them down or speed them up, which changes how much of a study drug stays in the body.
Studies list them so they can be avoided or switched; bring a list of everything you take, including supplements.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Absolute neutrophil count (ANC)
The number of neutrophils, white blood cells that help fight infection, in a given amount of blood. Too few raises the risk of infection.
It is a count, not a percentage of the white cells. Limits are written in units that mean the same: ≥ 1.5 × 10⁹/L is ≥ 1,500 per mm³ (µL). Each lab has its own reference range.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Platelets
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ULN (upper limit of normal)
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Bilirubin
A yellow substance made when red blood cells are broken down, which the liver clears. A high level can mean a problem with the liver or the bile ducts.
Criteria often allow more for people with Gilbert’s syndrome, a harmless inherited condition that raises bilirubin.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ALT and AST (liver enzymes)
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Patients receive sapanisertib as in Phase I. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: Sapanisertib
Patients receive pazopanib hydrochloride PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression may crossover to Arm I.
Drug: Pazopanib · Drug: Pazopanib Hydrochloride
Given PO
Also known as: GW786034
Given PO
Also known as: GW786034B, Votrient
Given PO
Also known as: INK-128, INK128, MLN-0128, MLN0128, TAK-228
Number of Phase I Participants With Dose-Limiting Toxicity Events (Phase I)
The Maximum Tolerated Dose (MTD) of sapanisertib (MLN0128) is defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients graded according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Dose-limiting toxicities include non-hematologic events graded 3 or higher and deemed at least possibly related to treatment. The number of patients reporting a dose-limiting event is reported.
Time frame: 28 days
Progression-free Survival (PFS) (Phase II Analysis Group 2 - Initial Treatment Period)
Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The median and an upper confidence boundary from a 1-sided, 85% confidence interval are estimated using the Kaplan-Meier methods.
Time frame: Up to 2 years
The Number of Patients Who Experienced Grade 3+ Adverse Events (Phase II Analysis Group 2 - Initial Treatment Period)
The number of patients who experienced grade 3+ adverse events for Phase II Analysis Group 2 for the initial treatment period is reported below.
Time frame: Up to 4 months
Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD], and Progressive Disease [PD])(Phase II Analysis Group 2 - Initial Treatment Period)
The frequencies (and percentages) of tumor response categories (CR, PR, SD, PD) will be summarized for Phase II Analysis Group 2. Complete Response (CR): All of the following must be true: a. Disappearance of all target lesions. b. Each target lymph node must have reduction in short axis to \< 1.0 cm. Partial Response (PR): At least a 30% decrease in PBSD taking as reference the BSD. Progression (PD): At least one of the following must be true: a. At least one new malignant lesion, b. At least a 20% increase in PBSD. c. PD via FDG-PET imaging. d. unequivocal progression of existing non-target lesions and non-target lymph nodes. e. symptomatic deterioration. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for PD taking as reference the MSD.
Time frame: Up to 2 years
Duration of Response (Phase II Analysis Group 2 - Initial Treatment Period)
Duration of response is defined as the time between each patient's best tumor response and progression (or date of last disease assessment for patients who die without progression or are lost to follow-up). Complete Response (CR): All of the following must be true: a. Disappearance of all target lesions. b. Each target lymph node must have reduction in short axis to \< 1.0 cm. Partial Response (PR): At least a 30% decrease in PBSD taking as reference the BSD.
Time frame: Time between each patient's best tumor response and progression(or date of last disease assessment for patients who die without progression or are lost to follow-up), assessed up to 2 years
Number of Patients Having CR, PR, or SD at 6 Months (Phase II Analysis Group 2 - Initial Treatment Period)
Will be defined as the number of patients having either complete response (CR), partial response (PR), or stable disease for at least 6 months after starting treatment. The frequencies and rates of tumor response categories (CR, PR, SD, PD, and too early/not evaluated) will be summarized by dose cohort and treatment arm. Complete Response (CR): All of the following must be true: a. Disappearance of all target lesions. b. Each target lymph node must have reduction in short axis to \< 1.0 cm. Partial Response (PR): At least a 30% decrease in PBSD taking as reference the BSD. Progression (PD): At least one of the following must be true: a. At least one new malignant lesion,b. At least a 20% increase in PBSD. c. PD via FDG-PET imaging. d. unequivocal progression of existing non-target lesions and non-target lymph nodes. e. symptomatic deterioration. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for PD taking as reference the MSD.
Time frame: Up to 6 months
Time to Progression (TTP) (Phase II Analysis Group 2 - Initial Treatment Period)
Time to progression is defined as the time between randomization and disease progression. Kaplan-Meier methodology will be used to estimate the distribution of TTP. Progression (PD): At least one of the following must be true: a. At least one new malignant lesion,b. At least a 20% increase in PBSD. c. PD via FDG-PET imaging. d. unequivocal progression of existing non-target lesions and non-target lymph nodes. e. Symptomatic deterioration.
Time frame: Time between randomization and disease progression, assessed up to 2 years
Overall Survival (OS) (Phase II Analysis Group 2 - Initial Treatment Period)
Overall survival (OS) (Phase II Analysis Group 2 - Initial Treatment Period). Kaplan-Meier methodology will be used to estimate the distribution of OS.
Time frame: Time between randomization and death due to any cause (or last contact for surviving patients and those lost to follow-up), assessed up to 2 years
Progression-free Survival (PFS) (Phase II)
Defined as either disease progression or death (in cases where patients have died without evidence of disease progression) in crossover patients.
Time frame: Up to 2 years
Duration of Response in Crossover Patients (Phase II)
Will be analyzed using Kaplan-Meier methodology.
Time frame: Time between each patient's best tumor response and progression>>> (or date of last disease assessment for patients who die without progression or are lost to follow-up), assessed up to 2 years
Time to Progression (TTP) in Crossover Patients (Phase II)
Kaplan-Meier methodology will be used to estimate the distribution of\>\>\> TTP.
Time frame: Time between date the patient initiated sapanisertib and disease progression, assessed up to 2 years
Overall Survival (OS) in Crossover Patients (Phase II)
Kaplan-Meier methodology will be used to estimate the distribution of\>\>\> OS.
Time frame: Time between date the patient initiated sapanisertib and death due to any cause (or last contact for surviving patients and those lost to follow-up), assessed up to 2 years
Cohort-specific Evaluation of 4-month Clinical Benefit Rate (CBR) (Phase II, Analysis Group II)
Analyses will be exploratory in nature.
Time frame: 4 months
| Milestone | Phase I - Dose Level 0 | Phase I - Dose Level 1 | Phase I - Dose Level 2 | Phase II - Analysis Group 1 Pazopanib | Phase II - Analysis Group 1 MLN0128 | Phase II - Analysis Group 2 Pazopanib | Phase II - Analysis Group 2 MLN0128 | Phase II - Analysis Group 1 Pazopanib Crossover | Phase II - Analysis Group 2 Pazopanib Crossover |
|---|---|---|---|---|---|---|---|---|---|
| Started | 4 | 4 | 4 | 6 | 13 | 15 | 56 | 6 | 43 |
| Completed | 3 | 3 | 3 | 6 | 12 | 13 | 55 | 6 | 43 |
| Not completed | 1 | 1 | 1 | 0 | 1 | 2 | 1 | 0 | 0 |
| Withdrew: Did not meet eligibility criteria | 1 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Withdrew: Withdrew before initiation of regimen | 0 | 0 | 0 | 0 | 1 | 2 | 1 | 0 | 0 |
| Milestone | Phase I - Dose Level 0 | Phase I - Dose Level 1 | Phase I - Dose Level 2 | Phase II - Analysis Group 1 Pazopanib | Phase II - Analysis Group 1 MLN0128 | Phase II - Analysis Group 2 Pazopanib | Phase II - Analysis Group 2 MLN0128 | Phase II - Analysis Group 1 Pazopanib Crossover | Phase II - Analysis Group 2 Pazopanib Crossover |
|---|---|---|---|---|---|---|---|---|---|
| Started | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 6 | 43 |
| Completed | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 4 | 26 |
| Not completed | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 17 |
The Maximum Tolerated Dose (MTD) of sapanisertib (MLN0128) is defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients graded according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Dose-limiting toxicities include non-hematologic events graded 3 or higher and deemed at least possibly related to treatment. The number of patients reporting a dose-limiting event is reported.
| Participants | Phase I - Dose Level 0 | Phase I - Dose Level 1 | Phase I - Dose Level 2 |
|---|---|---|---|
| Number of Phase I Participants With Dose-Limiting Toxicity Events (Phase I) | 0 | 0 | 0 |
Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The median and an upper confidence boundary from a 1-sided, 85% confidence interval are estimated using the Kaplan-Meier methods.
| months | Phase II - Analysis Group 2 MLN0128 | Phase II - Analysis Group 2 Pazopanib |
|---|---|---|
| Progression-free Survival (PFS) (Phase II Analysis Group 2 - Initial Treatment Period) | 2.0 (1.9 to 3.0) | 2.1 (1.9 to 3.7) |
The number of patients who experienced grade 3+ adverse events for Phase II Analysis Group 2 for the initial treatment period is reported below.
| Participants | Phase II - Analysis Group 2 MLN0128 | Phase II - Analysis Group 2 Pazopanib |
|---|---|---|
| The Number of Patients Who Experienced Grade 3+ Adverse Events (Phase II Analysis Group 2 - Initial Treatment Period) | 28 | 38 |
The frequencies (and percentages) of tumor response categories (CR, PR, SD, PD) will be summarized for Phase II Analysis Group 2. Complete Response (CR): All of the following must be true: a. Disappearance of all target lesions. b. Each target lymph node must have reduction in short axis to \< 1.0 cm. Partial Response (PR): At least a 30% decrease in PBSD taking as reference the BSD. Progression (PD): At least one of the following must be true: a. At least one new malignant lesion, b. At least a 20% increase in PBSD. c. PD via FDG-PET imaging. d. unequivocal progression of existing non-target lesions and non-target lymph nodes. e. symptomatic deterioration. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for PD taking as reference the MSD.
| Participants | Phase II - Analysis Group 2 MLN0128 | Phase II - Analysis Group 2 Pazopanib |
|---|---|---|
| Complete Response | 0 | 0 |
| Partial Response | 2 | 2 |
| Stable Disease | 14 | 23 |
| Progressive Disease | 28 | 26 |
Duration of response is defined as the time between each patient's best tumor response and progression (or date of last disease assessment for patients who die without progression or are lost to follow-up). Complete Response (CR): All of the following must be true: a. Disappearance of all target lesions. b. Each target lymph node must have reduction in short axis to \< 1.0 cm. Partial Response (PR): At least a 30% decrease in PBSD taking as reference the BSD.
| months | Phase II - Analysis Group 2 MLN0128 | Phase II - Analysis Group 2 Pazopanib |
|---|---|---|
| Duration of Response (Phase II Analysis Group 2 - Initial Treatment Period) | 0.9 (0 to 1.84) | 1.8 (0 to 3.6) |
Will be defined as the number of patients having either complete response (CR), partial response (PR), or stable disease for at least 6 months after starting treatment. The frequencies and rates of tumor response categories (CR, PR, SD, PD, and too early/not evaluated) will be summarized by dose cohort and treatment arm. Complete Response (CR): All of the following must be true: a. Disappearance of all target lesions. b. Each target lymph node must have reduction in short axis to \< 1.0 cm. Partial Response (PR): At least a 30% decrease in PBSD taking as reference the BSD. Progression (PD): At least one of the following must be true: a. At least one new malignant lesion,b. At least a 20% increase in PBSD. c. PD via FDG-PET imaging. d. unequivocal progression of existing non-target lesions and non-target lymph nodes. e. symptomatic deterioration. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for PD taking as reference the MSD.
| Participants | Phase II - Analysis Group 2 MLN0128 | Phase II - Analysis Group 2 Pazopanib |
|---|---|---|
| Number of Patients Having CR, PR, or SD at 6 Months (Phase II Analysis Group 2 - Initial Treatment Period) | 1 | 5 |
Time to progression is defined as the time between randomization and disease progression. Kaplan-Meier methodology will be used to estimate the distribution of TTP. Progression (PD): At least one of the following must be true: a. At least one new malignant lesion,b. At least a 20% increase in PBSD. c. PD via FDG-PET imaging. d. unequivocal progression of existing non-target lesions and non-target lymph nodes. e. Symptomatic deterioration.
| months | Phase II - Analysis Group 2 MLN0128 | Phase II - Analysis Group 2 Pazopanib |
|---|---|---|
| Time to Progression (TTP) (Phase II Analysis Group 2 - Initial Treatment Period) | 2.0 (1.9 to 3.0) | 2.1 (1.9 to 3.7) |
Overall survival (OS) (Phase II Analysis Group 2 - Initial Treatment Period). Kaplan-Meier methodology will be used to estimate the distribution of OS.
| months | Phase II - Analysis Group 2 MLN0128 | Phase II - Analysis Group 2 Pazopanib |
|---|---|---|
| Overall Survival (OS) (Phase II Analysis Group 2 - Initial Treatment Period) | 12.2 (7.5 to 16.3) | 13.7 (10.3 to NA) |
Defined as either disease progression or death (in cases where patients have died without evidence of disease progression) in crossover patients.
Results for this outcome have not been posted.
Will be analyzed using Kaplan-Meier methodology.
Results for this outcome have not been posted.
Kaplan-Meier methodology will be used to estimate the distribution of\>\>\> TTP.
Results for this outcome have not been posted.
Kaplan-Meier methodology will be used to estimate the distribution of\>\>\> OS.
Results for this outcome have not been posted.
Analyses will be exploratory in nature.
Results for this outcome have not been posted.
Collected over Up to 2 years. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Phase I - Dose Level 0 | 2/3 (66.7%) | 1/3 (33.3%) | 3/3 (100%) |
| Phase I - Dose Level 1 | 1/3 (33.3%) | 0/3 (0%) | 3/3 (100%) |
| Phase I - Dose Level 2 | 3/3 (100%) | 0/3 (0%) | 3/3 (100%) |
| Phase II - Analysis Group 1 MLN0128 | 9/12 (75%) | 5/12 (41.7%) | 12/12 (100%) |
| Phase II - Analysis Group 1 Pazopanib | 5/12 (41.7%) | 6/12 (50%) | 12/12 (100%) |
| Phase II - Analysis Group 2 MLN0128 | 27/55 (49.1%) | 20/55 (36.4%) | 54/55 (98.2%) |
| Phase II - Analysis Group 2 Pazopanib | 24/56 (42.9%) | 24/56 (42.9%) | 55/56 (98.2%) |
| Event | Phase I - Dose Level 0 | Phase I - Dose Level 1 | Phase I - Dose Level 2 | Phase II - Analysis Group 1 MLN0128 | Phase II - Analysis Group 1 Pazopanib | Phase II - Analysis Group 2 MLN0128 | Phase II - Analysis Group 2 Pazopanib |
|---|---|---|---|---|---|---|---|
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specifyNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 1/3 | 0/3 | 0/3 | 0/12 | 0/12 | 0/55 | 4/56 |
| Bronchopulmonary hemorrhageRespiratory, thoracic and mediastinal disorders | 1/3 | 0/3 | 0/3 | 0/12 | 0/12 | 0/55 | 0/56 |
| AnemiaBlood and lymphatic system disorders | 0/3 | 0/3 | 0/3 | 1/12 | 0/12 | 0/55 | 2/56 |
| Heart failureCardiac disorders | 0/3 | 0/3 | 0/3 | 0/12 | 1/12 | 0/55 | 0/56 |
| ConstipationGastrointestinal disorders | 0/3 | 0/3 | 0/3 | 0/12 | 1/12 | 0/55 | 0/56 |
| Gastrointestinal disorders - Other, specifyGastrointestinal disorders | 0/3 | 0/3 | 0/3 | 1/12 | 0/12 | 1/55 | 1/56 |
| NauseaGastrointestinal disorders | 0/3 | 0/3 | 0/3 | 1/12 | 0/12 | 1/55 | 1/56 |
| Small intestinal obstructionGastrointestinal disorders | 0/3 | 0/3 | 0/3 | 1/12 | 0/12 | 0/55 | 1/56 |
| VomitingGastrointestinal disorders | 0/3 | 0/3 | 0/3 | 1/12 | 0/12 | 1/55 | 1/56 |
| Death NOSGeneral disorders | 0/3 | 0/3 | 0/3 | 1/12 | 0/12 | 1/55 | 2/56 |
| Event | Phase I - Dose Level 0 | Phase I - Dose Level 1 | Phase I - Dose Level 2 | Phase II - Analysis Group 1 MLN0128 | Phase II - Analysis Group 1 Pazopanib | Phase II - Analysis Group 2 MLN0128 | Phase II - Analysis Group 2 Pazopanib |
|---|---|---|---|---|---|---|---|
| NauseaGastrointestinal disorders | 0/3 | 3/3 | 2/3 | 7/12 | 5/12 | 33/55 | 23/56 |
| FatigueGeneral disorders | 3/3 | 3/3 | 3/3 | 10/12 | 11/12 | 43/55 | 40/56 |
| White blood cell decreasedInvestigations | 0/3 | 3/3 | 1/3 | 1/12 | 3/12 | 4/55 | 7/56 |
| AnorexiaMetabolism and nutrition disorders | 0/3 | 1/3 | 3/3 | 5/12 | 6/12 | 32/55 | 22/56 |
| HyperglycemiaMetabolism and nutrition disorders | 2/3 | 2/3 | 1/3 | 9/12 | 2/12 | 27/55 | 14/56 |
| DiarrheaGastrointestinal disorders | 0/3 | 2/3 | 1/3 | 7/12 | 7/12 | 17/55 | 30/56 |
| VomitingGastrointestinal disorders | 0/3 | 1/3 | 2/3 | 6/12 | 3/12 | 19/55 | 15/56 |
| Platelet count decreasedInvestigations | 0/3 | 1/3 | 2/3 | 3/12 | 6/12 | 13/55 | 14/56 |
| Weight lossInvestigations | 0/3 | 1/3 | 2/3 | 2/12 | 2/12 | 9/55 | 11/56 |
| HeadacheNervous system disorders | 1/3 | 2/3 | 1/3 | 3/12 | 3/12 | 8/55 | 12/56 |
Registered Phase I patients and Randomized Phase II patients
| Age, Continuous(years) | Phase I - Dose Level 0 | Phase I - Dose Level 1 | Phase I - Dose Level 2 | Phase II - Analysis Group 1 MLN0128 | Phase II - Analysis Group 1 Pazopanib | Phase II - Analysis Group 2 MLN0128 | Phase II - Analysis Group 2 Pazopanib | Total |
|---|---|---|---|---|---|---|---|---|
| Mean | 47.3 ± 4.7 | 56.3 ± 12.3 | 48.7 ± 16.0 | 53.2 ± 11.2 | 53.0 ± 16.0 | 59.7 ± 13.4 | 55.7 ± 13.6 | 56.4 ± 13.5 |
| Sex: Female, Male(Participants) | Phase I - Dose Level 0 | Phase I - Dose Level 1 | Phase I - Dose Level 2 | Phase II - Analysis Group 1 MLN0128 | Phase II - Analysis Group 1 Pazopanib | Phase II - Analysis Group 2 MLN0128 | Phase II - Analysis Group 2 Pazopanib | Total |
|---|---|---|---|---|---|---|---|---|
| Female | 2 | 3 | 2 | 4 | 8 | 40 | 37 | 96 |
| Male | 1 | 0 | 1 | 9 | 4 | 16 | 21 | 52 |
| Race (NIH/OMB)(Participants) | Phase I - Dose Level 0 | Phase I - Dose Level 1 | Phase I - Dose Level 2 | Phase II - Analysis Group 1 MLN0128 | Phase II - Analysis Group 1 Pazopanib | Phase II - Analysis Group 2 MLN0128 | Phase II - Analysis Group 2 Pazopanib | Total |
|---|---|---|---|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 2 |
| Asian | 0 | 0 | 0 | 0 | 1 | 1 | 1 | 3 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Black or African American | 1 | 0 | 0 | 0 | 0 | 6 | 3 | 10 |
| White | 1 | 3 | 2 | 12 | 10 | 44 | 48 | 120 |
| More than one race | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Unknown or Not Reported | 1 | 0 | 1 | 1 | 0 | 4 | 6 | 13 |
| ECOG Performance Status(Participants) | Phase I - Dose Level 0 | Phase I - Dose Level 1 | Phase I - Dose Level 2 | Phase II - Analysis Group 1 MLN0128 | Phase II - Analysis Group 1 Pazopanib | Phase II - Analysis Group 2 MLN0128 | Phase II - Analysis Group 2 Pazopanib | Total |
|---|---|---|---|---|---|---|---|---|
| 0 | 1 | 2 | 1 | 8 | 9 | 35 | 28 | 84 |
| 1 | 2 | 1 | 2 | 5 | 3 | 21 | 30 | 64 |
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PDFs hosted by the registry, ClinicalTrials.gov.
Ran from Nov 2015 to primary completion in Dec 2018, 36 months.
Results were first posted in Mar 2020, 1 year 2 months after primary completion.
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Studies of the drugs tested here: Pazopanib · Sapanisertib
National Cancer Institute (NCI) →